Variant 22-35756109-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001349999.2(RBFOX2):c.1133T>C(p.Leu378Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RBFOX2
NM_001349999.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.04

Variant links:

Genes affected

RBFOX2 (HGNC:9906): (RNA binding fox-1 homolog 2) This gene is one of several human genes similar to the C. elegans gene Fox-1. This gene encodes an RNA binding protein that is thought to be a key regulator of alternative exon splicing in the nervous system and other cell types. The protein binds to a conserved UGCAUG element found downstream of many alternatively spliced exons and promotes inclusion of the alternative exon in mature transcripts. The protein also interacts with the estrogen receptor 1 transcription factor and regulates estrogen receptor 1 transcriptional activity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RBFOX2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX2	NM_001349999.2 linkuse as main transcript	c.1133T>C	p.Leu378Pro	missense_variant	11/14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RBFOX2	ENST00000695854.1 linkuse as main transcript	c.1133T>C	p.Leu378Pro	missense_variant	11/14		NM_001349999.2	ENSP00000512219.1	A0A8Q3WKT3
RBFOX2	ENST00000438146.7 linkuse as main transcript	c.1145T>C	p.Leu382Pro	missense_variant	11/14	1		ENSP00000413035.2	O43251-8
RBFOX2	ENST00000449924.6 linkuse as main transcript	c.932T>C	p.Leu311Pro	missense_variant	10/13	1		ENSP00000391670.2	O43251-10
RBFOX2	ENST00000414461.6 linkuse as main transcript	c.896+3779T>C		intron_variant		1		ENSP00000407855.2	O43251-4
RBFOX2	ENST00000695807.1 linkuse as main transcript	n.*385T>C		non_coding_transcript_exon_variant	11/15			ENSP00000512187.1	A0A8Q3SI31
RBFOX2	ENST00000695807.1 linkuse as main transcript	n.*385T>C		3_prime_UTR_variant	11/15			ENSP00000512187.1	A0A8Q3SI31
RBFOX2	ENST00000695805.1 linkuse as main transcript	n.*430+3779T>C		intron_variant				ENSP00000512185.1	A0A8Q3SI20

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1316628

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

648756

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 26, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with RBFOX2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 382 of the RBFOX2 protein (p.Leu382Pro). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

.;.;T;.;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.82

T;T;T;D;T;T

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.55

D;D;D;D;D;D

MetaSVM

Benign

-0.59

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.1

D;D;D;N;D;D

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Benign

0.17

T;T;T;T;T;T

Polyphen

0.0010

B;D;B;D;B;D

Vest4

0.85

MutPred

0.55

.;.;.;Loss of stability (P = 0.0485);.;.;

MVP

0.56

MPC

1.6

ClinPred

0.99

GERP RS

5.7

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over